Method for preparing carbostyril derivatives

ABSTRACT

Carbostyril derivatives useful as coccidiostats are prepared by reacting an ortho-halo benzaldehyde with a 2-alkyl-2-oxazoline, then heating at above about 200° C thereby forming the carbostyril.

This is a division of copending application Ser. No. 602,602 filed Aug.6, 1975, U.S. Pat. No. 4,006,148.

BACKGROUND OF THE INVENTION

This invention relates to carbostyril derivatives. In a particularaspect, this invention relates to carbostyril derivatives having utilityas coccidiostats.

Coccidiosis is a severe disease of poultry, especially chickens, andmany compounds have been developed for combatting it. However, thecausative organisms have the ability to develop resistance to suchcompounds to that after a period of use, most coccidiostats graduallylose their effectiveness and must be replaced. Accordingly there is acontinuing need for new, non-toxic coccidiostats.

SUMMARY OF THE INVENTION

It is an object of this invention to provide novel carbostyrilderivatives.

It is another object of this invention to provide carbostyrilderivatives having coccidiostat activity.

Other objects of this invention will be apparent to those skilled in theart.

It is the discovery of this invention to provide a novel process for thepreparation of carbostyril derivatives represented by formula I byreacting an o-haloaromatic aldehyde with a 2-substituted oxazoline:##STR1## R can be chloro, nitro, or dimethylamino and R¹ can behydrogen, alkyl, e.g. methyl, phenyl, p-methoxyphenyl, benzamido,2,4-dichlorophenoxy or acetamido. These carbostyrils can be readilyconverted to the corresponding 2-chloroquinolines if desired.

DETAILED DISCUSSION

According to the process of the present invention, an o-haloaromaticaldehyde represented by formula II: ##STR2## is reacted in a 1:1 moleratio with an oxazoline represented by formula III: ##STR3## R and R¹have the same meaning described above and X is a halogen atom, e.g.chloro- or bromo-.

The reactants are heated, preferably but not necessarily, in thepresence of an acidic catalyst, e.g. sodium bisulfate, in a suitablesolvent, e.g. a mixture of xylene or toluene with N-methylpyrrolidinone,dimethylformamide, decalin or tetralin, at reflux temperature. One moleof water is eliminated per mole of reactants, and when water stopscoming off, the mixture is further heated to remove the xylene andrefluxing is continued at 200°-300°, generally for from 15 min. to about2 hours. One mole equivalent of methallyl chloride is a by-product ofthe reaction and collects in the distillate. After the reaction iscomplete, the mixture is cooled and poured into water whereupon thecarbostyril product crystallizes. It is separated, e.g. by filtration,decantation or centrifugation, washed and dried. It can berecrystallized from acetic acid if further purification is desired.

It is known from H. L. Wehrmeister, J. Org. Chem. 27 4418 (1962), whichis incorporated herein by reference thereto, that aromatic aldehydesreact with 2-substituted-2-oxazolines to yield phenylethenyloxazolines.It is believed that such compounds are formed as intermediates in thepresent process during the water-elimination stage. Accordingly, it isanother embodiment of the present invention to prepare the carbostyrilderivatives by heating a phenylethenyloxazoline represented by theformula IV: ##STR4## at 200°-220° C for a period of time sufficient toform a carbostyril derivative.

The carbostyrils of the present invention can be further reacted withphosphorous oxychloride to form chloroquinoline derivatives.Accordingly, it is another embodiment of the present invention toprovide a novel process for the preparation of chloroquinolinederivatives.

Some of the compounds formed by the process of the present inventionpossess utility as coccidiostats. They are administered to poultry byincorporating them in the poultry feed at a concentration of about 200g/ton. The effective compounds are represented by formula I wherein R is5- or 7-chloro or 7-dimethylamino, and R¹ is hydrogen, methyl,acetamido, phenyl, p-methoxyphenyl or 2,4-dichlorophenoxy except thatwhen R is 7-chloro, R¹ cannot be hydrogen. More particularly, there arepreferred those compounds wherein R is 5- or 7-chloro and R¹ is hydrogenor phenyl and their corresponding quinolines. The especially preferredcompounds include but are not limited to:

P-1983-- 2,7-dichloro-3-phenylquinoline

P-1995-- 2,5-dichloroquinoline

P-2000-- 7-chloro-3-phenylcarbostyril

P-2001--5-chlorocarbostyril

The invention will be better understood with reference to the followingexamples. It is understood that the examples are intended only forpurposes of illustrating the invention and it is not intended that theinvention be limited thereby.

EXAMPLE 1

A stirred mixture of 2-benzyl-4,4-dimethyl-2-oxazoline (18.9 g., 0.1mole), 2,4-dichlorobenzaldehyde (17.5 g., 0.1 mole) and 1 g. of sodiumbisulfate in 50 ml. of N-methylpyrrolidinone and 30 ml. of xylene washeated at reflux under a short column, water separator (20 ml.), andcondenser. Distillation to the separator occurred at a pot temperatureof 177°-199° C. A total of 18 ml. of distillate was then drained fromthe separator intermittently during 1.25 hours with the pot temperatureultimately reaching 218°. Refluxing near 218° was continued anadditional 15 minutes. The reaction mixture was cooled, then dilutedwith 300 ml. of water and filtered. The solid product was washed with 2× 100 ml. water and 2 × 50 ml. of methanol and dried in a vacuumdesiccator. There was obtained 21.4 g. (84%) of7-chloro-3-phenylcarbostyril, m.p. 252°-253°. Recrystallization from 200ml. of acetic acid gave 15.1 g., m.p. 252°-255°.

Analysis Calcd. for C₁₅ H₁₀ ClNO: C, 70.45; H, 3.94; Cl, 13.87; N, 5.48.Found: C, 70.36; H, 3.73; Cl, 13.60; N, 5.51.

The compound (P-2000) was used to combat coccidiosis in chicks. Chickstarter rations were prepared according to the following formula:

    ______________________________________                                        INGREDIENTS                                                                   Ground yellow corn    52.5%                                                   Soybean meal 44%      39.0%                                                   Deh. alfalfa meal 17% 2.5%                                                    Corn oil              3.0%                                                    Salt                  .5%                                                     CaCo.sub.3            1.0%                                                    Dical, 24% Ca 21%P    2.0%                                                    DL-Methionine         .1%                                                     Trace mineral mix     .05%                                                    Vitamin premix        .25%                                                    Calculated Analysis                                                           Protein %             22.0                                                    *Me kcal/lb           1400                                                    Calcium %             1.0                                                     Phosp. total %        .80                                                     Avail. %              .54                                                     ______________________________________                                         *metabolizeable energy                                                   

A group of 20 broiler chicks, 2 weeks old, of mixed sex were chosen forthe experiment. Half of them were controls, fed the above ration, andhalf were fed the above rations plus 200 g/ton of7-chloro-3-phenylcarbostyril. On the second day of the test, each birdwas orally inoculated with 1 cc of sporulated oocysts of Eimeria tenellacontaining approximately 100,000 oocysts per 1 cc. The results are givenin Table 1.

                  Table 1                                                         ______________________________________                                                        Untreated Treated                                             ______________________________________                                        Morbidity at 6 days, %                                                                          100         100                                             Total bloody droppings                                                                          158         91                                              Total mortality   5/10        1/10                                            Av. body weight gain                                                                            108 g/bird  54 g/bird                                       ______________________________________                                    

It was concluded that the compound is effective for combattingcoccidiosis when present in the feed at a concentration of about 200g/ton.

EXAMPLE 2

A stirred mixture of 5.0 g. of 7-chloro-3phenylcarbostyril (P-2000,prepared according to Example 1) and 25 ml. of POCl.sub. 3 was heated atreflux for 3 hours and then evaporated on a rotary evaporator finally at90°, 20 mm. The residue in 200 ml. benzene was washed with 150 ml. 3%(w/v) aqueous sodium bicarbonate solution, dried with anhydrous Na₂SO.sub. 4, and evaporated to yield 5.3 g. of product, m.p. 99°-100° C.Recrystallization from hexane-benzene gave 4.1 g. of2,7-dichloro-3-phenylquinoline, P-1983, m.p. 102°-103°. The elementalanalyses are given in Table 4.

The product was used to combat coccidiosis in chicks following the sameprocedure as described in Example 1. The results are given in Table 2.

                  Table 2                                                         ______________________________________                                                       Controls  Treated                                              ______________________________________                                        Morbidity at 6 days, %                                                                         100          50                                              Total bloody droppings                                                                         100          33                                              Total mortality  6/10         2/10                                            Postmortem lesions                                                                             6/6         2/2                                              Av. body weight gain                                                                           --          119 g/bird                                       ______________________________________                                    

It was concluded that P-1983 is effective for combatting coccidiosiswhen present in the feed at a concentration of about 200 g/ton

EXAMPLES 3-8

The experiment of Example 1 was repeated in all essential details exceptthat the values for R and R¹ in the aldehydes and the oxazolinesemployed were selected as follows:

                  Table 3                                                         ______________________________________                                                       Aldehyde    Oxazoline                                          Example No.    R           R.sup.1                                            ______________________________________                                        3              5-Cl        H                                                  4              5-Cl        Ph                                                 5              6-NO.sub.2  Ph                                                 6              (CH.sub.3).sub.2 N                                                                        Ph                                                 7              7-Cl        p-MeOPh*                                           8              7-Cl        2,4-Cl.sub.2 PhO**                                 ______________________________________                                         *p-methoxyphenyl                                                              **2,4-dichlorophenoxy                                                    

The compounds obtained are listed in Table 4.

Compounds P-2001 and P-1999 were tested as cocciodstats following theprocedure of Example 1. Of the chicks receiving P-2001, there were sixsurvivors out of ten. The morbidity was 50% and there were 72 bloodydroppings. The weight gain averaged 125 g/chick. Compound P-2001 wasconcluded to be useful in combatting cocidiosis.

Compound P-1999 was ineffective.

The coccidiostat test described in Example 1 is repeated four timesexcept that P-2000 is omitted and there is substituted therefor P-2007,P-2011, P-2012, and P-2015 respectively. Treated chicks infected withthe coccidiosis-producing organism show a significant survival rate. Itis concluded that each of the compounds is useful as a coccidiostat.

EXAMPLE 9

2-Acetamidomethyl-4,4-dimethyl-2-oxazoline was obtained by reactingN-acetylglycine with 2-amino-2-methyl-1-propanol. The oxazoline was thenreacted with 2,4-dichlorobenzaldehyde in accordance with the experimentof Example 1. The resulting compound, 3-acetamido-7-chlorocarbostyril(P-2014) is listed in Table 4.

The coccidiostat test described in Example 1 is repeated in allessential details except that P-2014 is substituted for P-2000. Treatedchicks infected with the coccidiosis-producing organism show asignificant survival rate. It is concluded that each of the compounds isuseful as a coccidiostat.

                                      Table 4                                     __________________________________________________________________________     ##STR5##                                                                                                          Analyses, %                              Ex.             Code                                                                              Yield            Calcd.      Found                        No.                                                                              R     R'      No.                                                                              %   m.p. ° C                                                                     Formula                                                                              C  H  N  Cl C   H  N  Cl                 __________________________________________________________________________    3  5-Cl  H      P-2001                                                                            21  289-291                                                                             C.sub.9 H.sub.6 ClNO                                                                 60.18                                                                            3.37                                                                              7.80                                                                            19.74                                                                            60.00                                                                             3.17                                                                              7.67                                                                            19.20              4  5-Cl  Ph     P-2011                                                                            91  261.5-262.5                                                                         C.sub.15 H.sub.10 ClNO                                                               70.45                                                                            3.94                                                                              5.48                                                                            13.87                                                                            70.53                                                                             3.97                                                                              5.32                                                                            13.43              5  6-NO.sub.2                                                                          Ph     P-1999                                                                            95  299-302                                                                             C.sub.15 H.sub.10 N.sub.2 O.sub.3                                                    67.65                                                                            3.79                                                                             10.52                                                                            -- 67.33                                                                             3.88                                                                             10.04                                                                            --                 6  7-(CH.sub.3).sub.2 N                                                                Ph     P-2012                                                                            33  249-255                                                                             C.sub.17 H.sub.16 N.sub.2 O                                                          77.24                                                                            6.10                                                                             10.60                                                                            -- 76.73                                                                             6.02                                                                             10.78                                                                            --                 7  7-Cl  p-MeOPh                                                                              P-2007                                                                            67  261-263                                                                             C.sub.16 H.sub.12 ClNO.sub.2                                                         67.26                                                                            4.24                                                                              4.90                                                                            12.41                                                                            66.92                                                                             4.09                                                                              4.87                                                                            12.54              8  7-Cl  2,4-Cl.sub.2 PhO                                                                     P-2015                                                                            19  290-291                                                                             C.sub.15 H.sub.8 Cl.sub.3 NO.sub.2                                                   52.89                                                                            2.37                                                                              4.11                                                                            31.23                                                                            52.65                                                                             2.30                                                                              3.96                                                                            31.09              9  7-Cl                                                                                 ##STR6##                                                                            P-2014                                                                            36  325-338                                                                             C.sub.11 H.sub.9 ClN.sub.2 O.sub.2                                                   55.82                                                                            3.83                                                                             11.84                                                                            14.98                                                                            55.16                                                                             4.03                                                                             11.49                                                                            14.56              __________________________________________________________________________

EXAMPLE 10

3-Methylcarbostyril (P-2018) is a known compound (F. Effenberger and W.Hartmann, Chem. Ber., 102, 3260 (1969)). It was prepared from2-[2-(2-chlorophenyl)-1 methyl-ethenyl]-4,4-dimethyl-2-oxazoline byheating the oxazoline at 194°-268° C for 1.5 hours. The residue wascrystallized from ethanol. Recrystallized product had a melting point of240°-241° compared with the literature value of 238° in accordance withthe procedure of Example 1.

A 5 g. portion was heated at reflux in 25 ml of POCl₃ for 3 hours. Theresulting solution was diluted with 5-10 ml of toluene and evaporated ona rotary evapoator at water pump pressure. To the residue was added 25ml of toluene and again evaporated. The residue was extracted with 2 ×50 ml of hot chloroform which, on evaporation, gave 5.6 q. residue whichwas crystallized from 22 ml of methanol to yield 1.2 g. of2-chloro-3-phenyl-quinoline, P-1996, m.p. 56-56.5°.

Analysis: Calculated for C₁₅ H₁₀ ClN: C, 75.16; H, 4.21; Cl, 14.79; N,5.84. Found: C, 75.21' H, 4.51; Cl, 14.79; N, 5.36. The infra-redabsorption spectrum was consistent with the expected structure.

EXAMPLES 11-14

The experiment of Example 10 was repeated four times in all essentialdetails except that in place of 3-methyl-carbostyril there wassubstituted, respectively, the carbostyrils of Examples 3, 4, 5 and 7.The resulting quinolines thereby obtained (Table 5) were:

Example 11--2,5-Dichloroquinoline (P-1995) from P-2001.

Example 12--2,5-Dichloro-3-phenylquinoline (P-1997) from P-2011.

Example 13--2-Chloro-6-nitro-3-phenylquinoline (P-1998) from P-1999.

Example 14--2,7-Dichloro-3-p-methoxyphenylquinoline (P-2002) fromP-2007.

These compounds were tested as coccidiostats at 200 g/ton of feed by theprocedure described in Example 1. Of 10 chicks receiving P-1995, allbirds survived. There were 158 bloody droppings with a morbidity of 70%.The gain in weight averaged 119 g. per bird. It was concluded thatP-1995 was useful as a coccidiostat, P-1997, P- 1998 and P-2002 wereineffective as coccidiostats.

                                      Table 5                                     __________________________________________________________________________     ##STR7##                                                                                                           Analyses, %                                                                   Calcd.      Found                       Ex. No.                                                                             R    R'    Code No.                                                                            m.p. ° C                                                                      Formula C  H  N  Cl C  H  N  Cl                 __________________________________________________________________________    2     7-Cl Ph    P-1983                                                                              102-103                                                                              C.sub.15 H.sub.9 Cl.sub.2 N                                                           65.72                                                                            3.31                                                                             5.11                                                                             25.87                                                                            65.70                                                                            3.26                                                                             5.05                                                                             26.14              11    5-Cl H     P-1995                                                                              78 - 78.5                                                                            C.sub.9 H.sub.5 Cl.sub.2 N                                                            54.58                                                                            2.54                                                                             7.07                                                                             35.80                                                                            54.91                                                                            2.69                                                                             7.02                                                                             35.64              12    5-Cl Ph    P-1997                                                                              133 - 134                                                                            C.sub.15 H.sub.9 Cl.sub.2 N                                                           65.72                                                                            3.31                                                                             5.11                                                                             25.87                                                                            65.22                                                                            3.26                                                                             5.29                                                                             25.34              13    6-NO.sub.2                                                                         Ph    P-1998                                                                              212 - 212.5                                                                          C.sub.15 H.sub.9 ClN.sub.2 O.sub.2                                                    63.28                                                                            3.19                                                                             9.84                                                                             12.46                                                                            63.37                                                                            3.30                                                                             9.47                                                                             11.59              14    7-Cl p-MeOPh                                                                             P-2002                                                                              126 - 127.5                                                                          C.sub.16 H.sub.11 Cl.sub.2 NO                                                         63.18                                                                            3.65                                                                             4.61                                                                             23.31                                                                            63.48                                                                            3.58                                                                             4.47                                                                             23.03              __________________________________________________________________________

EXAMPLE 15

2-[2-(2,4-Dichlorophenyl)-1-methylethenyl]-4,4 -dimethyl-2-oxazoline(P-2016) was prepared by reacting 2,4-dichlorobenzaldehyde with4,4-dimethyl-2-ethyl-2-oxazoline in the presence of iodine catalyst.

P-2016, 40 g., was heated under nitrogen at 205°-295° for 2 hours whilecollecting the distillate. The residue was crystallized from 850 ml. ofhot methanol to yield 10.5 g. of 7-chloro-3-methyl carbostyril, m.p.240°-241°. It was designated P-2008. Methallyl chloride was identifiedin the distillate.

P-2008 is tested for coccidiostat activity according to the proceduredescribed in Example 1. Treated chicks infected with thecoccidiosis-producing organism show a significant survival rate,indicating that P-2008 is a useful coccidiostat.

EXAMPLE 16

The experiment of Example 1 was repeated in all essential details exceptthat 2-bromobenzaldehyde was substituted for 2,4-dichlorobenzaldehyde ona mole for mole basis. There was obtained 3-phenylcarbostyril, a knowncompound, in 31% yield.

I claim:
 1. A method for preparing carbostyril derivatives representedby the formula: ##STR8## where R is 5 or 7-chloro, or 7-dimethylaminoand R¹ is hydrogen, methyl, phenyl, p-methoxyphenyl, acetamido or2,4-dichlorophenoxy with the proviso that when R is 7-chloro, R¹ cannotbe hydrogen comprising the step of heating at 200°-220° C aphenylethenyl oxazoline represented by the formula ##STR9## wherein X isa chlorine or bromine atom and R and R¹ have the same meanings definedabove until said carbostyril derivative is formed.
 2. The method ofclaim 1 wherein R is chloro.
 3. The method of claim 1 wherein R isdimethylamino.
 4. The method of claim 1 wherein R¹ is hydrogen.
 5. Themethod of claim 1 wherein R¹ is methyl.
 6. The method of claim 1 whereinR¹ is phenyl.
 7. The method of claim 1 wherein R¹ is p-methoxyphenyl. 8.The method of claim 1 wherein R¹ is acetamido.
 9. The method of claim 1wherein R¹ is 2,4-dichlorophenoxy.
 10. The method of claim 1 wherein Xis chlorine.
 11. The method of claim 1 wherein X is bromine.